Microbiology FDA 483 (Eugia Pharma Specialities): Procedures to prevent microbiological contamination sterile drug product are not established and followed

Observation

Procedures designed to prevent microbiological contamination of drug products purporting to be sterile are not established and followed

Facility Type

Sterile Manufacturing

Firm / Company

Eugia Pharma Specialities Limited

System

Details

(1) During aseptic filling operations, procedure EP2-PRD-SOP-002, “Personnel Behaviour in Aseptic Area” and line specific intervention procedures were not followed:
(A) During aseptic filling of *** Injection:
(i) On April 16, 2024, for line assembly and filling on your *** Line, U.S. market  batch *** Injection ***gram/vial, operators were observed performing an *** manual intervention where they used *** to assemble the *** (Intervention I-1.3) used to *** dispense *** of sterile *** into the empty sterile vial on the filling line. During this step of set up the operator’s arms and upper torso were also observed reaching over the line blocking laminar air flow. This practice was consistent with that observed during line assembly for ROW *** Injection, batches ***. A similar intervention was observed during media fill batch *** conducted in July of 2022 and determined by investigation APL-AN-PNC-22-0125 to be the root cause of a contaminated vial and subsequent media fill failure.
(ii) During aseptic filling on April 17, 2024, *** gram/vial, US batch *** the operator was observed using the non-sterile RABs *** to perform intervention C-3, “Adjustment of fill weight”, where *** were placed into and around the *** used to dispense the sterile *** into each vial. This same intervention was observed and performed in the same manner during the filling of ROW *** Injection, batches ***.
(iii) On April 16, 2024, operators were observed performing an *** intervention to change out the canister of sterile *** from an empty canister to a full canister. This intervention involves numerous manual manipulations where the operator uses *** and where their arms and upper body are over the filling line and stopper track with exposed stoppers. This intervention is performed up to *** times during aseptic filling of ***. Operators were also observed using *** to manually wipe spilled *** off the filling line following this intervention.
(B) During filling of *** Injection on *** lines ***.
(i) During intervention C-67 “Removal of Fallen Vial From Conveyor Before *** on *** line *** operators were observed to touch the rim of an open vial with the RABS *** during batch ***. The vial was subsequently left on the line and filled. In other instances of this intervention during batches *** the RABS *** closely passed directly over open vials that were not removed. The RABS *** are removed *** for *** but otherwise remain on the line where they are sanitized, but not sterilized.
(ii) During interventions to remove fallen vials at the *** operators used the RABS *** directly over open vials that were not subsequently removed. For example, this occurred during aseptic filling of: *** Injection batches manufactured on *** line *** including US market batches *** and *** Injection batches manufactured on *** line *** including EU market batches ***.
(iii) During *** of stoppers (intervention I-3) and removal of jammed *** stoppers (intervention C-17) on line *** the operator was observed to use the RABS *** directly over sterile stoppers and the surfaces of the sterile stopper bowl. For example, during aseptic filling of *** Injection US market batches ***.
(iv) On April 25, 2024, while observing an operator performing area cleaning in the Grade A and Grade B areas of line *** where vials are aseptically filled, *** the operator’s donned sterile gowning was observed to have a hole in the back of the gown on the left side.
(C) During aseptic canister filling of bulk *** batch *** (EU market) :
(i) Operators placed forceps and *** in a *** in the *** laminar airflow (LAF) during aseptic sampling of filled containers. The operator reached over the tools and rested their hands directly above the tools before using the *** to sample sterile product and the forceps to open the sterile canister by contacting the primary closure *** stopper. Additionally, the operator was observed to place the *** cap and stopper on the sampling vials or base of the LAF and then reach over it before replacing the product contact stopper on the canister. This sampling of filled containers of *** bulk occurs approximately *** times *** batch during US market batches.
(ii) The sterile canisters used for filling bulk *** were placed on a stool outside of the barrier for opening and closing, rather than on the *** as specified in procedure EP2-PBA-SOP-065. During *** and placing of the open canister on the *** the operator was observed to reach across and disrupt *** laminar airflow near the open sterile canisters.
(D) During aseptic filling of bulk *** API into sterile canisters:
(i) *** filling, *** filled canister is opened in a *** LAF for sampling. The operator places sterile forceps and *** that contact the product and primary closure in the sampling *** and leans over these items during operations.
(ii) The operator appeared to lean their body near the open container during removal and placing of the *** stopper and while reaching for the *** line.
(2) Four batches of *** Injection required corrective interventions to replace ***  after *** seized due to build up of sterile product leaking from the *** and drying, causing sticking, following filling line stoppages. Change control CPL-AN-CC-23-0092 (closed June 29, 2023 , implemented the spraying of the *** with sterile *** throughout the batch whenever the *** surfaces staff to dry. For example, for *** Injection batches it occurred seven times during US market batch *** and six times during EU market batch ***.
The change did not include an assessment to identify an appropriate way to prevent leaking or to apply a lubricant that would not rapidly dry and require repeated interventions during the aseptic filling operations to reapply it. The intervention was approved without evaluating the new intervention in the smoke studies on ***.
During batches *** operators did not follow intervention procedure that require filling to be stopped while performing this intervention of spraying *** on the ***.

Record Date

05/2024

FEI Number

3009883410

Country

India

Citation Type

483

Audit Duration (Days)

7

Investigators

Anastasia M Shields, Justin A Boyd, Vaishali J Patel

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Disclaimer: The purpose of this article is to provide helpful information on FDA 483s related to microbiological issues. This article represents 483 information in Tabular form for quick access and easy navigation. Information for this article is derived from “Form FDA 483” (Inspectional Observation). This article is not intended to replace the information provided by the FDA, nor is it guaranteed to be complete, always refer official FDA site for details.

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Alarm 1 Aseptic Behavior 30 Aseptic Technique 49 Autoclave 1 Biological Indicator 1 Building Maintenance 6 Calibration 1 Clean Room 15 Clean Room Practices 36 Cleaning and Sanitization 29 Cleaning Validation 1 Computerized System 4 Contamination 13 Contemporaneous Verification 1 Data Integrity Issue 10 Disinfectant Efficacy 2 Disinfection 15 Drug Product 1 Endotoxin 1 Environment monitoring 16 Equipment Cleaning 6 Equipment Operation 13 Facilities And Equipment System 13 Facility Design 5 Follow-Up Findings 2 General Cleaning 3 Good documentation Practices 4 Gowning 3 HEPA 4 Hold Time Study 2 HVAC 6 Influx of lesser quality air 1 Investigation 12 Investigation inadequate 5 Investigation incomplete 3 Laboratory Controls 17 Laboratory Practice 16 Maintenance 10 Manufacturing control 9 Media Fill 15 Method Transfer 2 Method Validation 5 Microbial Identification 1 Microbiological Contaminationn 10 No Procedure followed 14 Non-Conformance 1 OOS 5 Personnel Monitoring 3 Procedure 32 Qualification 32 Quality System 33 Risk assessment 6 Service Vendor Audit 1 Smoke studies 14 Specifications 5 Stability Study 2 Sterile Drug Products 5 Sterility Testing 1 sterilizati 2 Sterilization 3 Suitability 1 test procedure 0 Test Procedure (SOP) 10 Trends 1 Usage log 1 Validation 37 Visual Inspection 1 Warehouse 2 Water System 1

Microbiology FDA 483 (Jiangsu Hengrui Pharmceuticals): Container closure systems do not provide adequate protection against foreseeable external factors

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Product contact equipment including *** stopper drums, *** were sterilized without outer wrapping and transferred from Grade A cart to Inside of the RABS without cover in Workshop *** Filling Room ***.

Microbiology FDA 483 (Jubilant Radiopharmacies): The movement of first air in the ISO 5 area is blocked or disrupted

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Surface monitoring of the filling and stoppering machine is not performed in a timely manner following the completion of aseptic filling operations to ensure the data is representative of the environmental conditions at the time of filling. For example:

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On April 29, 2024, *** cleaning wipes packed and ready to be used for *** aseptic cleaning in the Grade A area of the *** Injection *** filling line *** had loose threads and fibers them. The same wipes are also used for *** cleaning in the *** Injection manufacturing line ***. Upon receiving, the wipes are not inspected for the presence of loose threads and fibers.
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